Proteomic signatures to identify pathways underlying the progression to heart failure

蛋白质组学特征可识别心力衰竭进展的潜在途径

• 批准号: 10895160
• 负责人: Amil M Shah
• 金额: $ 76.31万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10895160
• 关键词: Address; Affect; Age; Atherosclerosis Risk in Communities; Biological; Biological Assay; Biological Markers; Bradykinin; Cardiovascular system; Data; Databases; Development; Disease; EFRAC; Elderly; Epidemiology; Ethnic Origin; Failure; Fibrosis; Frequencies; Functional disorder; Funding; Future; Genetic; Genetic Determinism; Genetic Variation; Genomics; Genotype; Goals; Heart failure; Hypertrophy; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention Studies; Left Ventricular Ejection Fraction; Mass Spectrum Analysis; Measures; Mediator; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Outcome; Participant; Pathway interactions; Phenotype; Physiologic pulse; Predictive Value; Prevention; Proteins; Proteomics; Public Health; Research; Research Proposals; Risk; Risk Marker; Role; Structure; Sympathetic Nervous System; System; TNF gene; Transforming Growth Factor beta; Translating; Validation; Visit; adjudication; aptamer; biomarker identification; biracial; candidate identification; circulating biomarkers; cohort; defined contribution; effective intervention; effective therapy; genetic variant; genome sequencing; genomic data; heart function; human data; improved; innovation; interstitial; metabolomics; mortality; multi-ethnic; novel; novel marker; phenotypic data; precision medicine; preservation; prevent; preventive intervention; prognostic; prospective; proteomic signature; pulmonary vascular disorder; risk prediction; saluretic; systemic inflammatory response; targeted agent; therapeutic target; translational study; whole genome

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular ejection fraction (HFpEF). Neurohormonal blockade has not proven efficacious for HFpEF, and no disease-specific therapy currently exists. There is an urgent need for novel targetable pathways, and basic/translational data implicate systemic inflammation as a potential unexploited therapeutic target, although human data is limited. The objective of this application is to define the contributions of inflammatory pathways to, and identify novel causal pathways for, the development of cardiac dysfunction and overt HF in the elderly. The central hypothesis is that specific inflammatory and neurohormonal pathways will differentially predict progressive LV dysfunction and incident HF phenotype (HFpEF vs HFrEF) in late life, and that detailed longitudinal proteomic and phenotypic data will allow for discovery of novel biologic pathways and prognostic risk markers for HF. Aptamer-based proteomics provide precise quantification of 4,931 circulating proteins and unprecedented profiling of relevant inflammatory and non-inflammatory pathways. Employing rigorous epidemiologic approaches, we will combine large-scale proteomics with detailed longitudinal cardiovascular phenotyping (echo, pulse wave velocity) and prospective HF adjudication in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort to address the following specific aims: 1) To identify individual circulating proteins and protein networks that predict incident HF and HF phenotype (HFpEF vs HFrEF); 2) To determine proteins and protein networks associated with longitudinal worsening of LV diastolic and systolic function; 3) To identify candidate proteins and protein networks most likely to be mediators of progressive LV dysfunction and HF using genomic data. The contributions of the proposed research will be to clarify the role of inflammatory – relative to neurohormonal – pathways for HF development and to discover novel mediators of HF in late life. These contributions will be significant because by determining the importance of pathways targeted by several existing agents, our findings could rapidly translate into novel preventative interventions for HF – an essential step to decrease HF-associated morbidity and mortality. This research proposal is fundamentally innovative in: (1) focusing on large-scale circulating proteomics to understand HFpEF pathobiology, with simultaneous assessment of inflammatory, neurohormonal, and novel pathways in a cohort at risk for HFpEF to prevent HF development; (2) integrating proteomic and genomic data to identify candidate proteins and pathways that are HF risk mediators as opposed to risk markers; and (3) assessing novel antecedents to HFpEF beyond hypertrophy and diastolic dysfunction, including impaired LV strain, pulmonary vascular dysfunction, and RV dysfunction. This project is expected to provide an original, integrated understanding of the biologic pathways promoting HFpEF, providing a conceptual framework for future mechanistic and translational studies of HFpEF pathobiology.

心力衰竭（HF）不成比例地影响老年人，主要发展为HF并保留左

项目成果

Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies.

• DOI: 10.1038/s41588-022-01051-w
• 发表时间: 2022-05
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Zhang, Jingning;Dutta, Diptavo;Koettgen, Anna;Tin, Adrienne;Schlosser, Pascal;Grams, Morgan E.;Harvey, Benjamin;Yu, Bing;Boerwinkle, Eric;Coresh, Josef;Chatterjee, Nilanjan
• 通讯作者: Chatterjee, Nilanjan